CN110787161B - New application of thiazole compound in resisting fish virus - Google Patents
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- CN110787161B CN110787161B CN201910884132.8A CN201910884132A CN110787161B CN 110787161 B CN110787161 B CN 110787161B CN 201910884132 A CN201910884132 A CN 201910884132A CN 110787161 B CN110787161 B CN 110787161B
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention discloses a new application of a thiazole compound in fish virus resistance, wherein the thiazole compound is nitazoxanide, and the structural formula of the compound is shown as a formula 1:
Description
Technical Field
The invention relates to a novel application of thiazole compounds, in particular to a novel application of the thiazole compounds in resisting fish viruses.
Background
Nitazoxanide is a thiazolidine compound, and is firstly synthesized on the frame of an antiparasitic compound niclosamide in the seventies of the twentieth century (Rossgnol 1975). Nitazoxanide was originally marketed in mexico and the united states as an active ingredient of antiparasitic drugs, and was subsequently found to have good antiviral activity in cell models, animal models, and human clinical trials. The research shows that the nitazoxanide has good treatment effect on infection of a plurality of respiratory viruses such as influenza viruses H1N1 and H7N9 and non-respiratory viruses such as liver viruses HBV and HCV. However, the antiviral effect of nitazoxanide on fish viruses is rarely reported.
Studies on antiviral mechanisms have shown that nitazoxanide is able to inhibit different stages of viral proliferation, depending on the characteristics of the virus and the host cell. For vaccinia virus (vaccinia virus), nitazoxanide is able to inhibit replication of the viral genome (Hickson, marginetantu et al 2018). For the kiruguinya virus (chikungunya virus), nitazoxanide inhibits the virus adsorption process and the virus release process (Wang, Lu et al 2016). In the case of Hepatitis C Virus (HCV), nitazoxanide activates PKR protein kinase in cells, phosphorylates eukaryotic initiation factor eIF2 alpha, initiates cellular innate immune response, and inhibits virus proliferation in cells (Rosssignol 2014). However, the antiviral mechanism of nitazoxanide against fish viruses is still under study.
Viral Hemorrhagic Septicemia (VHS) is a virulent infectious disease of fish caused by VHSV (VHSV). The VHSV has wide host range, can infect economic fishes such as salmon, trout, turbot and the like, causes severe hemorrhagic septicemia, and has high mortality rate of diseased fishes. In virology research, scholars at home and abroad clearly know the genomic structure and evolutionary relationship of VHSV.
VHSV is known to belong to Rhabdoviridae (Rhabdoviridae) as a minus-strand RNA virus having a total genome length of 11kb and expressing 6 genes in the order of 3 'to 5'. VHSV can be subdivided into four classes of virus strains (Pereiro, Figures et al 2016) based on genomic differences. Although the virology of the virus is known to some extent through domestic and foreign research, the research on the host immune response pathway is not thorough and deep enough for the interaction mechanism of the virus and the host, which hinders the development process of novel aquatic drugs. VHS is mainly prevalent in europe, north america, japan and korea, has caused a serious economic loss, and is one of aquatic epidemic diseases that must be reported to the world animal health organization after an epidemic situation occurs. In the last decade, scientists successively discover and separate VHSV from various Pacific wild marine fishes, and detect VHSV from various cultured fishes in China, such as economic fishes like largemouth bass and the like. Although the harm of the VHSV is huge, an effective VHSV vaccine is still lacking in the current market, and epidemic disease prevention and control mainly takes strict monitoring and prevention, so that the research and development of the VHSV-resistant medicine are beneficial to improving the quality and international competitiveness of aquaculture fish in China and assisting the healthy development of the aquaculture industry.
Disclosure of Invention
The invention aims to provide a novel application of thiazole compounds in resisting fish viruses.
In order to achieve the purpose, the invention provides the technical scheme that: the thiazole compound is new application of resisting fish viruses, and is nitazoxanide, and the structural formula of the thiazole compound is shown in a formula 1:
the thiazole compound is tizoxanide, and the structural formula of the tizoxanide is shown as a formula 2:
the thiazole compound comprises geometrical isomers of nitazoxanide/tizoxanide, pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof.
The pharmaceutically acceptable salts thereof include inorganic or organic acid salts thereof, and inorganic or organic base salts thereof.
The pharmaceutically acceptable salts thereof include sodium salts, potassium salts, calcium salts, lithium salts, meglumine salts, hydrochloride salts, hydroabietate salts, rosasite salts, nitrate salts, sulfate salts, bisulfate salts, phosphate salts, hydrogen phosphate salts, acetate salts, propionate salts, butyrate salts, oxalate salts, pivalate salts, adipate salts, alginate salts, lactate salts, citrate salts, tartrate salts, succinate salts, maleate salts, fumarate salts, picrate salts, aspartate salts, gluconate salts, benzoate salts, methanesulfonate salts, ethanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate salts and/or pamoate salts. But are not limited to the above salt forms.
The thiazole compounds are used for inhibiting the proliferation of Viral Hemorrhagic Septicemia Virus (VHSV) in phoxinus scaphocephala epithelial cells (FHM) cells and eliminating cytopathic effects (CPE).
The thiazole compound can obviously slow down CPE of cells caused by virus infection, inhibit virus proliferation on FHM cells and reduce the copy number of virus genes in the cells
The thiazole compounds reduce the CPE degree of VHSV infected cells in micromolar concentration in an in vitro antiviral experiment.
The thiazole compounds reduce the copy number of viral genes in VHSV infected cells at micromolar concentrations.
The thiazole compounds are used for preventing invasion of VHSV into FHM cells.
Drawings
FIG. 1 is a graph of the effect of nitazoxanide at different concentrations on the protection of the activity of VHSV infected FHM cells;
FIG. 2 is a graph of the effect of ribavirin on the protection of VHSV infected FHM cell activity at different concentrations;
FIG. 3 is a graph of the effect of nitazoxanide and tizoxanide in very significantly reducing the copy number of viral genes in FHM cells infected with VHSV infection;
FIG. 4 is an effect diagram that nitazoxanide can inhibit the process of VHSV invading FHM cells, and significantly reduce the copy number of virus genes in FHM cells infected with VHSV;
figure 5 is a graph of the effect of nitazoxanide significantly slowing CPE of FHM cells infected with VHSV; wherein A is 8 μ M nitazoxanide treated group, B is 8 μ M ribavirin treated group, and C is DMSO treated group.
Detailed Description
The following claims are provided to illustrate the present invention in a more detailed description, but not by way of limitation.
Example 1: toxicity testing of nitazoxanide and ribavirin on FHM cells.
(1) FHM cell culture
FHM cells used in the experimental process are stored in the laboratory, and the source and the passage number are clear. The complete cell culture medium used for cell growth was M199 medium at 10% serum concentration, the maintenance medium used for acute challenge experiments was M199 medium at 2% serum concentration, and serum-free M199 medium was used for dilution of virus and compounds. The cells were cultured in an incubator at 28 ℃ and passaged by trypsinizing the cells with 0.25% EDTA for 2 minutes, usually at a concentration of 1:2 to 1:3, in cell culture flasks, and about 16 hours later, the cells were confluent as a monolayer.
(2) Cell viability assay
Cell Counting Kit-8 from MCE was used to detect Cell activity. Digesting FHM cells paved at the bottom of the bottle for 2 minutes by using 0.25% EDTA pancreatin, preparing single cell suspension by using a complete culture medium after digestion is finished, diluting the serum concentration of the complete culture medium to 2% by using a serum-free culture medium, counting the cells, and inoculating the cells to a 96-well plate at the density of 10000 cells/hole, wherein the using amount of the culture medium is 100 mu L/hole. In an incubator at 28 ℃The culture was carried out for 16 hours. Nitazoxanide and ribavirin were diluted with serum-free medium and added to 96-well plates to final concentrations of 0.25. mu.M, 0.5. mu.M, 1. mu.M, 2. mu.M, 4. mu.M, 8. mu.M, 16. mu.M and 32. mu.M. A drug-free cell blank and a cell-free media control were set. After treating the cells for 48 hours, the supernatant was discarded and the maintenance medium was replaced. The cells were incubated with CCK-8 reagent (10. mu.L) in each well, and the cells were developed in the dark for 4 hours, and OD was detected using a living cell imager from BioTek 450 。
The cytotoxicity of nifedipine and ribavirin for FHM was calculated using the following formula:
example 2: nitazoxanide and tizoxanide protect FHM cell activity experiments.
Cell activity was measured using Cell Counting Kit-8 from MCE. Digesting FHM cells paved at the bottom of the bottle for 2 minutes by using 0.25% EDTA pancreatin, preparing single cell suspension by using a complete culture medium for suspending after the digestion is finished, diluting the serum concentration of the complete culture medium to 2% by using a serum-free culture medium, inoculating the cells to a 96-well plate at the density of 10000 cells/hole after cell counting, and culturing for 16 hours in an incubator at 28 ℃. VHSV was diluted with serum-free M199 Medium and added to 96-well plates to give a virus concentration of 50TCID 50 . Nitazoxanide was diluted into 96-well plates to final concentrations of 0.25. mu.M, 0.5. mu.M, 1. mu.M, 2. mu.M, 8. mu.M, 16. mu.M and 32. mu.M, and a cell blank without drug and virus and a negative control without drug and with virus were set. After treating the cells for 24 hours, the supernatant was discarded, and the maintenance medium was replaced with 100. mu.L/well of the medium. The cells were added with 10. mu.L of CCK-8 reagent per well, developed in the dark for 4 hours, and OD was measured using a live cell imager from BioTek 450 。
The protective effect of the drug on the cell activity, i.e., the inhibition rate of viral proliferation, was calculated using the following formula:
the half effective concentration of nitazoxanide was calculated using GraphPad Prism 8.0 software.
Example 3: nitazoxanide and tizoxanide can reduce the copy number of virus genes in FHM cells infected with VHSV and slow down CPE experiments.
(1) Acute toxicity attack and drug treatment
Digesting FHM cells paved at the bottom of the flask for 2 minutes by using 0.25% EDTA pancreatin, preparing a single cell suspension by using a complete medium after digestion is finished, diluting the complete medium serum concentration to 2% by using a serum-free medium, counting the cells, and then counting the cells by 1.5X 10 5 The cells/well density were seeded into 12-well plates and incubated for 16 hours at 28 ℃ in an incubator. Diluting VHSV with serum-free medium, adding into 12-well plate cell to make VHSV final concentration 50TCID 50 . Nitazoxanide and ribavirin were diluted with serum-free medium and added to the 12-well plate cells to a final concentration of 8 μ M.
(2) Observe and take pictures of cells
After the cells subjected to the challenge were cultured in an incubator at 28 ℃ for 24 hours, the cells were observed using an inverted fluorescence microscope manufactured by Carl Zeiss AG company and a representative visual field was photographed under a 10-fold microscope. As shown in FIG. 5, the cells of the nitazoxanide-treated group were normal and showed no CPE, whereas those of the DMSO-treated group and ribavirin-treated group showed a large amount of CPE such as cell aggregation, rounding, floating death, etc.
(3) Cellular RNA extraction
1) Collecting cells: cells in 12-well plates were digested with 0.25% EDTA, resuspended in maintenance medium, and collected in rnase-free centrifuge tubes.
2) Cell lysis: centrifuge at 1300rpm for 2 minutes at room temperature, discard the supernatant, flick the tube to disperse the cell pellet, and add 500. mu.L of 4 ℃ pre-cooled Trizol reagent per tube.
3) Protein extraction: add 100. mu.L of chloroform to each tube, shake vigorously, and stand at room temperature for 5 minutes.
4) RNA isolation: after centrifugation at 13000rpm for 15 minutes at 4 ℃ 260. mu.L of the supernatant was transferred to a new RNase-free centrifuge tube.
5) And (3) RNA precipitation: add 260. mu.L of isopropanol to each tube, mix gently, and let stand at room temperature for 10 minutes.
6) RNA isolation: after centrifugation at 13000rpm for 12 minutes at 4 ℃ the supernatant was discarded.
7) And (3) washing the RNA precipitate: each tube was filled with 800. mu.L of 75% ethanol solution in DEPC water.
8) RNA isolation: centrifuging at 7600rpm at 4 deg.C for 7 min, discarding ethanol solution, and drying at room temperature for 10 min.
9) RNA dissolution: add 10. mu.L of RNase-free water to each tube to dissolve the RNA pellet.
10) And (3) measuring the concentration and purity of the RNA sample: RNA sample concentration and purity were determined using a Nanodrop instrument.
(4) Reverse transcription of RNA
The reverse transcription kit (PrimeScript) manufactured by TaKaRa company was used for the experiments TM RT reagent Kit with gDNA Eraser) for RNA reverse transcription, as follows.
1) Removal of gDNA: RNA samples of each experimental group were collected, and 2. mu.g of each RNA sample was subjected to reverse transcription. Firstly, adding 5 XgDNA Eraser Buffer (2 mu L) into RNA of each experimental group, complementing a reaction system to 10 mu L by RNase-free water, fully and uniformly mixing, and removing gDNA possibly existing in a sample by water bath at 42 ℃ for 2 min;
2) reverse transcription: adding 1 mu L of Mix enzyme solution, 1 mu L of primer Mix and 4 mu L of reaction buffer solution into the sample obtained in the step (1), complementing the volume to 20 mu L by RNase-free water, and putting the mixture into a PCR instrument for reverse transcription to obtain cDNA. The reverse transcription procedure was 15 minutes at 37 ℃ and 5 seconds at 85 ℃.
(5) Quantitative PCR and data processing
Quantitative PCR Using the GoTaq qPCR Master Mix kit manufactured by Promega, the procedure was as follows:
FHM beta-actin gene is selected as an internal reference gene. The quantitative PCR reaction system is a 10 mu L system: mu.L of template, 0.5. mu.L of each of the upstream and downstream primers, 5. mu.L of 2 Xmix enzyme solution, and 3. mu.L of RNase-free water. The amplification conditions were 40 cycles, 95 ℃ for 15 seconds, 60 ℃ for 15 seconds, and 72 ℃ for 15 seconds. After the experiment was completed, use 2 -ΔΔCT The method performs relative quantification and calculates the copy number of the viral gene in each group of cells. Histograms were drawn using GraphPad Prism 8.0 software.
Example 4: nitazoxanide inhibits the process experiment of invading FHM cells.
(1) Acute toxicity attack and drug treatment
Digesting FHM cells paved at the bottom of the flask for 2 minutes by using 0.25% EDTA pancreatin, preparing a single cell suspension by using a complete medium after digestion is finished, diluting the complete medium serum concentration to 2% by using a serum-free medium, counting the cells, and then counting the cells by 1.5X 10 5 The cells/well density were seeded into 12-well plates and incubated for 16 hours at 28 ℃ in an incubator. And (3) diluting the VHSV, the nitazoxanide and the ribavirin by using a serum-free culture medium, and placing the diluted VHSV, the nitazoxanide and the ribavirin and FHM cells into a refrigerator for precooling for 1 hour at 4 ℃. Pre-cooled VHSV was added to FHM cells to give a final virus concentration of 50TCID 50 . The cells after the challenge were placed in a refrigerator at 4 ℃ and the VHSV was allowed to adsorb FHM cells for 4 hours. FHM cells were washed 3 times with 4 ℃ pre-cooled PBS solution, the maintenance medium was changed and nitazoxanide and ribavirin were added to a final concentration of 8. mu.M. The cells were incubated in an incubator at 28 ℃ for 24 hours.
(2) Extracting cell RNA: the specific procedure is the same as in example 3.
(4) RNA reverse transcription: the specific procedure is the same as in example 3.
(5) Quantitative PCR and data processing: the specific procedure is the same as in example 3.
The results of the above examples 1-4 are analyzed in detail in FIGS. 1-5, wherein:
figure 1 shows that nitazoxanide is able to protect the activity of FHM cells infected with VHSV at a concentration of 8 μ M. Nitazoxanide can be used for treating 50TCID at different concentrations 50 FHM cell Activity in VHSV infection at well produces protection, half the Effective Concentration (EC) 50 ) 1.190. + -. 0.521. mu.M. The nitazoxanide antiviral effect has concentration dependent effect at concentration of 0-8 μ M. Because the compound has certain toxicity, the protection effect of nitazoxanide is weakened when the concentration is more than 8 mu M.
Figure 2 shows that ribavirin is able to protect the FHM cell activity of VHSV infection at a concentration of 8 μ M. Ribavirin can treat 50TCID at different concentrations 50 FHM cell Activity in VHSV infection in well protected, half the Effective Concentration (EC) 50 ) It was 0.6421. + -. 0.189. mu.M.
Figure 3 shows that nitazoxanide and tizoxanide are able to very significantly reduce the viral gene copy number in FHM cells infected with VHSV infection. In the figure, N is nitazoxanide, R is ribavirin which is known to have antiviral activity, and D is a solvent DMSO. 8 μ M of different compounds with 50TCID 50 VHSV/well was added to FHM cells simultaneously, and the number of copies of viral genes in cells of nitazoxanide-treated group after 24 hours and 36 hours of viral infection was significantly lower than that of DMSO-treated group (p < 0.001). Ribavirin loses its protective effect over 36 hours.
Figure 4 shows that nitazoxanide can inhibit the invasion process of VHSV into FHM cells, significantly reducing the copy number of viral genes in FHM cells infected with VHSV. N is nitazoxanide treatment, R is positive control ribavirin treatment, and D is negative control DMSO treatment. 50TCID 50 VHSV was adsorbed to FHM cells at 4 ℃ and then washed away with PBS to remove free virus, cells were treated with 8. mu.M compound for 4 hours, washed away with PBS to remove free virus, and cultured at 28 ℃ for 24 hours to determine the number of copies of viral genes in the cells. Both nitazoxanide and ribavirin can reduce the gene copy number in cell obviously (p is less than 0.01).
Figure 5 shows that nitazoxanide significantly slowed CPE of FHM cells infected with VHSV. A was 8. mu.M nitazoxanide-treated group, B was 8. mu.M ribavirin-treated group, and C was DMSO-treated group. The virus concentration is 50TCID 50 A hole. After the cells were cultured at 28 ℃ for 36 hours, significant CPE appeared in the DMSO control group and ribavirin-treated group, but the cells were in good condition in the nitazoxanide-treated group. The picture scale is 50 μm.
Claims (10)
1. The thiazole compound is used for preparing a medicine for resisting viral hemorrhagic septicemia virus, and is characterized in that the thiazole compound is nitazoxanide, and the structural formula of the nitazoxanide is shown as a formula 1:
2. the use of thiazole compounds according to claim 1 for preparing a medicament against viral hemorrhagic septicemia virus, wherein said thiazole compound is tizoxanide, the formula of which is shown in formula 2:
3. use of thiazole compounds according to any one of claims 1 to 2 for the preparation of a medicament against viral hemorrhagic septicaemia virus, wherein said thiazole compounds comprise a pharmaceutically acceptable salt of nitazoxanide/tizoxanide.
4. Use of thiazole compounds according to claim 3 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said pharmaceutically acceptable salts include inorganic or organic acid salts and inorganic or organic base salts thereof.
5. Use of thiazole compounds according to claim 4 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said pharmaceutically acceptable salts include sodium, potassium, calcium, lithium, meglumine, hydrochloride, hydrabamate, hydrarginate, nitrate, sulfate, bisulfate, phosphate, biphosphate, acetate, propionate, butyrate, oxalate, pivalate, adipate, alginate, lactate, citrate, tartrate, succinate, maleate, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and/or pamoate.
6. The use of thiazole compounds according to claim 3 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said thiazole compounds are used for inhibiting the proliferation of viral hemorrhagic septicemia virus in the epithelial cells of phoxinus lagowskii and eliminating cytopathic effect.
7. The use of thiazole compounds as claimed in claim 3 for preparing a medicament for treating viral hemorrhagic septicemia virus, wherein said thiazole compounds can significantly slow down cytopathic effect of cells caused by viral infection, and inhibit the proliferation of virus on the epithelial cells of phoxinus fatuae, thereby reducing the copy number of viral genes in the cells.
8. Use of thiazole compounds according to claim 3 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said thiazole compounds reduce the extent of the cytopathic effect of viral hemorrhagic septicemia virus infected cells in micromolar concentrations in an in vitro antiviral assay.
9. Use of thiazole compounds according to claim 3 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said thiazole compounds reduce the viral gene copy number in cells infected with viral hemorrhagic septicemia virus at micromolar concentrations.
10. Use of thiazole compounds according to claim 3 for the preparation of a medicament against viral hemorrhagic septicemia virus, wherein said thiazole compounds are used for preventing the invasion of viral hemorrhagic septicemia virus into the epithelial cells of phoxinus adiposa.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107536838A (en) * | 2016-06-24 | 2018-01-05 | 中国人民解放军军事医学科学院毒物药物研究所 | The application of Nitazoxanide and its activity form tizoxanide in terms of zika virus infection is treated |
| CN108289961A (en) * | 2016-03-31 | 2018-07-17 | 罗马克实验室有限公司 | Thiazides compound for treating viral infection |
| WO2018227228A1 (en) * | 2017-06-13 | 2018-12-20 | Commonwealth Scientific And Industrial Research Organisation | Antiviral drugs |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108289961A (en) * | 2016-03-31 | 2018-07-17 | 罗马克实验室有限公司 | Thiazides compound for treating viral infection |
| CN107536838A (en) * | 2016-06-24 | 2018-01-05 | 中国人民解放军军事医学科学院毒物药物研究所 | The application of Nitazoxanide and its activity form tizoxanide in terms of zika virus infection is treated |
| WO2018227228A1 (en) * | 2017-06-13 | 2018-12-20 | Commonwealth Scientific And Industrial Research Organisation | Antiviral drugs |
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| The use of nitazoxanide against the pathogensIchthyophthirius multifiliis and Aeromonas hydrophila in silvercatfish (Rhamdia quelen);Fernando J. Sutili等;《Veterinary Parasitology》;20131231;第197卷;摘要 * |
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